tbuckley/cabot-search huggingface dataset:
Incidence of Primary End Point Changes Among Active Cancer Phase 3 Randomized Clinical Trials
Authors: Marcus A. Florez, Joseph Abi Jaoude, Roshal R. Patel, Ramez Kouzy, Timothy A. Lin, Brian De, Esther J. Beck, Cullen M. Taniguchi, Bruce D. Minsky, Clifton D. Fuller, J. Jack Lee, Michael Kupferman, Kanwal P. Raghav, Michael J. Overman, Charles R. Thomas, Ethan B. Ludmir
Journal: JAMA Network Open (2023)

Importance Primary end point (PEP) changes to an active clinical trial raise questions regarding trial quality and the risk of outcome reporting bias. It is unknown how the frequency and transparency of the reported changes depend on reporting method and whether the PEP changes are associated with trial positivity (ie, the trial met the prespecified statistical threshold for PEP positivity). Objectives To assess the frequency of reported PEP changes in oncology randomized clinical trials (RCTs) and whether these changes are associated with trial positivity. Design, Setting, and Participants This cross-sectional study used publicly available data for complete oncology phase 3 RCTs registered in ClinicalTrials.gov from inception through February 2020. Main Outcomes and Measures The main outcome was change between the initial PEP and the final reported PEP, assessed using 3 methods: (1) history of tracked changes on ClinicalTrials.gov, (2) self-reported changes noted in the article, and (3) changes reported within the protocol, including all available protocol documents. Logistic regression analyses were performed to evaluate whether PEP changes were associated with US Food and Drug Administration approval or trial positivity. Results Of 755 included trials, 145 (19.2%) had PEP changes found by at least 1 of the 3 detection methods. Of the 145 trials with PEP changes, 102 (70.3%) did not have PEP changes disclosed within the manuscript. There was significant variability in rates of PEP detection by each method ( χ 2 = 72.1; P &amp;amp;lt; .001). Across all methods, PEP changes were detected at higher rates when multiple versions of the protocol (47 of 148 [31.8%]) were available compared with 1 version (22 of 134 [16.4%]) or no protocol (76 of 473 [16.1%]) ( χ 2 = 18.7; P &amp;amp;lt; .001). Multivariable analysis demonstrated that PEP changes were associated with trial positivity (odds ratio, 1.86; 95% CI, 1.25-2.82; P = .003). Conclusions and Relevance This cross-sectional study revealed substantial rates of PEP changes among active RCTs; PEP changes were markedly underreported in published articles and mostly occurred after reported study completion dates. Significant discrepancies in the rate of detected PEP changes call into question the role of increased protocol transparency and completeness in identifying key changes occurring in active trials.
Structure of coagulation factor VIII bound to a patient-derived anti-C1 domain antibody inhibitor
Authors: Kenneth C Childers, Nathan G Avery, Kevin Alexander Estrada Alamo, Omar Davulcu, Rose Marie Haynes, Pete Lollar, Christopher B. Doering, Carmen Helena Coxon, Paul Clinton Spiegel
Journal: Blood (2023)

The development of pathogenic antibody inhibitors against coagulation factor VIII (FVIII) occurs in approximately 30% of congenital hemophilia A patients receiving FVIII replacement therapy as well as in all cases of acquired hemophilia A. KM33 is an anti-C1 domain antibody inhibitor previously isolated from a severe hemophilia A patient. In addition to potently blocking FVIII binding to von Willebrand factor and phospholipid surfaces, KM33 disrupts FVIII binding to lipoprotein receptor-related protein 1 (LRP1), which drives FVIII hepatic clearance and antigen presentation in dendritic cells. Here, we report on the structure of FVIII bound to NB33, a recombinant derivative of KM33, by single-particle cryo-electron microscopy. Structural analysis reveals the NB33 epitope localizes to FVIII residues R2090-S2094 and I2158-R2159 which constitute membrane-binding loops in the C1 domain. Further analysis reveals multiple FVIII lysine and arginine residues, previously shown to mediate binding to LRP1, dock onto an acidic cleft at the NB33 variable domain interface, thus blocking a putative LRP1 binding site. Together, these results demonstrate a novel mechanism of FVIII inhibition by a patient-derived antibody inhibitor and provide structural evidence toward engineering FVIII with reduced LRP1-mediated clearance.
Pausing Endocrine Therapy for Pregnancy After Breast Cancer Found Safe
Authors: Emily Harris
Journal: JAMA (2023)

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Associations Between Vascular Risk Factor Levels and Cognitive Decline Among Stroke Survivors
Authors: Deborah A. Levine, Bingxin Chen, Andrzej T. Galecki, Alden L. Gross, Emily M. Briceño, Rachael T. Whitney, Robert J. Ploutz-Snyder, Bruno J. Giordani, Jeremy B. Sussman, James F. Burke, Ronald M. Lazar, Virginia J. Howard, Hugo J. Aparicio, Alexa S. Beiser, Mitchell S. V. Elkind, Rebecca F. Gottesman, Silvia Koton, Sarah T. Pendlebury, Anu Sharma, Mellanie V. Springer, Sudha Seshadri, Jose R. Romero, Rodney A. Hayward
Journal: JAMA Network Open (2023)

Importance Incident stroke is associated with accelerated cognitive decline. Whether poststroke vascular risk factor levels are associated with faster cognitive decline is uncertain. Objective To evaluate associations of poststroke systolic blood pressure (SBP), glucose, and low-density lipoprotein (LDL) cholesterol levels with cognitive decline. Design, Setting, and Participants Individual participant data meta-analysis of 4 US cohort studies (conducted 1971-2019). Linear mixed-effects models estimated changes in cognition after incident stroke. Median (IQR) follow-up was 4.7 (2.6-7.9) years. Analysis began August 2021 and was completed March 2023. Exposures Time-dependent cumulative mean poststroke SBP, glucose, and LDL cholesterol levels. Main Outcomes and Measures The primary outcome was change in global cognition. Secondary outcomes were change in executive function and memory. Outcomes were standardized as t scores (mean [SD], 50 [10]); a 1-point difference represents a 0.1-SD difference in cognition. Results A total of 1120 eligible dementia-free individuals with incident stroke were identified; 982 (87.7%) had available covariate data and 138 (12.3%) were excluded for missing covariate data. Of the 982, 480 (48.9%) were female individuals, and 289 (29.4%) were Black individuals. The median age at incident stroke was 74.6 (IQR, 69.1-79.8; range, 44.1-96.4) years. Cumulative mean poststroke SBP and LDL cholesterol levels were not associated with any cognitive outcome. However, after accounting for cumulative mean poststroke SBP and LDL cholesterol levels, higher cumulative mean poststroke glucose level was associated with faster decline in global cognition (−0.04 points/y faster per each 10–mg/dL increase [95% CI, −0.08 to −0.001 points/y]; P = .046) but not executive function or memory. After restricting to 798 participants with apolipoprotein E4 (APOE4) data and controlling for APOE4 and APOE4 × time, higher cumulative mean poststroke glucose level was associated with a faster decline in global cognition in models without and with adjustment for cumulative mean poststroke SBP and LDL cholesterol levels (−0.05 points/y faster per 10–mg/dL increase [95% CI, −0.09 to −0.01 points/y]; P = .01; −0.07 points/y faster per 10–mg/dL increase [95% CI, −0.11 to −0.03 points/y]; P = .002) but not executive function or memory declines. Conclusions and Relevance In this cohort study, higher poststroke glucose levels were associated with faster global cognitive decline. We found no evidence that poststroke LDL cholesterol and SBP levels were associated with cognitive decline.
Considerations Regarding Antipsychotic Drug Prescriptions Among People With Dementia During the COVID-19 Pandemic—Reply
Authors: Hao Luo, Kenneth K. C. Man, Ian C. K. Wong
Journal: JAMA Psychiatry (2023)

Third, the supplement of the study by Straus et al 1 notes that surveys were administered 6 times within the 8-week assessment period, while the time points when participants received the survey were not mentioned.For example, consider the pain assessment: The supplement lists the question asking patients to rate their pain at its worst in the last 24 hours.Research shows that the pain system exhibits circadian rhythms through different mechanisms, 5 and pain sensitivity may differ according to the time of day.Therefore, participants may report different pain severity depending on the time of day they complete the survey.Observation bias must be considered.Above all, this study contributes to the understanding of the utility of wrist-wearable devices in assessment of adverse posttraumatic neuropsychiatric sequelae.It is recommended that future studies include strict blinding methods, investigate patients' underlying medical conditions, and conduct selfreport symptom surveys at consistent time points.
Correction: ERS/ESICM/ESCMID/ALAT guidelines for the management of severe community-acquired pneumonia
Authors: Ignacio Martin-Loeches, Antoni Torres, Blin Nagavci, Stefano Aliberti, Massimo Antonelli, Matteo Bassetti, Lieuwe D. Bos, James D. Chalmers, Lennie Derde, Jan De Waele, Jose Garnacho-Montero, Marin Kollef, Carlos M. Luna, Rosario Menendez, Michael S. Niederman, Dmitry Ponomarev, Marcos I. Restrepo, David Rigau, Marcus J. Schultz, Emmanuel Weiss, Tobias Welte, Richard Wunderink
Journal: Intensive Care Medicine (2023)
Ccr2+ Monocyte-Derived Macrophages Influence Trajectories of Acquired Therapy Resistance in <i>Braf</i>-Mutant Melanoma
Authors: Dahihm Kim, Luye An, Jiwon Moon, Viviana I. Maymi, Alexander I. McGurk, Brian D. Rudd, Deborah J. Fowell, Andrew C. White
Journal: Cancer Research (2023)

Abstract Therapies targeting oncogene addiction have had a tremendous impact on tumor growth and patient outcome, but drug resistance continues to be problematic. One approach to deal with the challenge of resistance entails extending anticancer treatments beyond targeting cancer cells by additionally altering the tumor microenvironment. Understanding how the tumor microenvironment contributes to the evolution of diverse resistance pathways could aid in the design of sequential treatments that can elicit and take advantage of a predictable resistance trajectory. Tumor-associated macrophages often support neoplastic growth and are frequently the most abundant immune cell found in tumors. Here, we used clinically relevant in vivo Braf-mutant melanoma models with fluorescent markers to track the stage-specific changes in macrophages under targeted therapy with Braf/Mek inhibitors and assessed the dynamic evolution of the macrophage population generated by therapy pressure-induced stress. During the onset of a drug-tolerant persister state, Ccr2+ monocyte-derived macrophage infiltration rose, suggesting that macrophage influx at this point could facilitate the onset of stable drug resistance that melanoma cells show after several weeks of treatment. Comparison of melanomas that develop in a Ccr2-proficient or -deficient microenvironment demonstrated that lack of melanoma infiltrating Ccr2+ macrophages delayed onset of resistance and shifted melanoma cell evolution towards unstable resistance. Unstable resistance was characterized by sensitivity to targeted therapy when factors from the microenvironment were lost. Importantly, this phenotype was reversed by coculturing melanoma cells with Ccr2+ macrophages. Overall, this study demonstrates that the development of resistance may be directed by altering the tumor microenvironment to improve treatment timing and the probability of relapse. Significance: Ccr2+ melanoma macrophages that are active in tumors during the drug-tolerant persister state following targeted therapy-induced regression are key contributors directing melanoma cell reprogramming toward specific therapeutic resistance trajectories.
Considerations Regarding Antipsychotic Drug Prescriptions Among People With Dementia During the COVID-19 Pandemic
Authors: Wei-Min Chu, Chin-Ming Liu, James Cheng-Chung Wei
Journal: JAMA Psychiatry (2023)

To the Editor We read with great interest the article by Luo et al,1 which reports that the rate of antipsychotic medication prescriptions among older adults with dementia increased in 6 countries during the COVID-19 pandemic. However, we would like to highlight some key concerns.
Metformin Reprograms Tryptophan Metabolism to Stimulate CD8+ T-cell Function in Colorectal Cancer
Authors: Xiaowen Huang, Tiantian Sun, Jilin Wang, Xialu Hong, Huimin Chen, Tingting Yan, Chengbei Zhou, Danfeng Sun, Chen Yang, TaChung Yu, Wenyu Su, Wan Du, Hua Xiong
Journal: Cancer Research (2023)

Abstract Colorectal carcinogenesis coincides with immune cell dysfunction. Metformin has been reported to play a role in stimulating antitumor immunity, suggesting it could be used to overcome immunosuppression in colorectal cancer. Herein, using single-cell RNA sequencing (scRNA-seq), we showed that metformin remodels the immune landscape of colorectal cancer. In particular, metformin treatment expanded the proportion of CD8+ T cells and potentiated their function. Analysis of the metabolic activities of cells in the colorectal cancer tumor microenvironment (TME) at a single-cell resolution demonstrated that metformin reprogrammed tryptophan metabolism, which was reduced in colorectal cancer cells and increased in CD8+ T cells. Untreated colorectal cancer cells outcompeted CD8+ T cells for tryptophan, leading to impaired CD8+ T-cell function. Metformin in turn reduced tryptophan uptake by colorectal cancer cells, thereby restoring tryptophan availability for CD8+ T cells and increasing their cytotoxicity. Metformin inhibited tryptophan uptake in colorectal cancer cells by downregulating MYC, which led to a reduction in the tryptophan transporter SLC7A5. This work highlights metformin as an essential regulator of T-cell antitumor immunity by reprogramming tryptophan metabolism, suggesting it could be a potential immunotherapeutic strategy for treating colorectal cancer. Significance: Analysis of the impact of metformin on the colorectal cancer immunometabolic landscape at a single-cell resolution shows that metformin alters cancer cell tryptophan metabolism to stimulate CD8+ T-cell antitumor activity.
Short-Term Outcomes of Tricuspid Edge-to-Edge Repair in Clinical Practice
Authors: Philipp Lurz, Christian Besler, Thomas Schmitz, Raffi Bekeredjian, Georg Nickenig, Helge Möllmann, Ralph Stephan von Bardeleben, Alexander Schmeisser, Iskandar Atmowihardjo, Rodrigo Estevez-Loureiro, Edith Lubos, Megan Heitkemper, Dina Huang, Harald Lapp, Erwan Donal, Marianna Adamo, Paolo Golino, Bruno Melica, Volker Rudolph, Roberto Corti, Xavier Freixa, Dabit Arzamendi, Fabien Praz, Fausto Castriota, Karsten Veien, Marek Kowalski, Bernard Rensing, Niklas Schofer, Andreas Zirlik, Wolfgang Rottbauer
Journal: Journal of the American College of Cardiology (2023)

Severe tricuspid regurgitation (TR) is known to be associated with substantial morbidity and mortality.The authors sought to study the acute outcomes of subjects treated by tricuspid transcatheter edge-to-edge repair with the TriClip system (Abbott) in a contemporary, real-world setting.The bRIGHT (An Observational Real-World Study Evaluating Severe Tricuspid Regurgitation Patients Treated With the Abbott TriClip™ Device) postapproval study is a prospective, single-arm, open-label, multicenter, postmarket registry conducted at 26 sites in Europe. Echocardiographic assessment was performed at a core laboratory.Enrolled subjects were elderly (79 ± 7 years of age) with significant comorbidities. Eighty-eight percent had baseline massive or torrential TR, and 80% of subjects were in NYHA functional class III or IV. Successful device implantation occurred in 99% of subjects, and TR was reduced to ≤moderate at 30 days in 77%. Associated significant improvements in NYHA functional class (I/II, 20% to 79%; P < 0.0001) and Kansas City Cardiomyopathy Questionnaire score (19 ± 23 points improvement; P < 0.0001) were observed at 30 days. With baseline TR grade removed as a variable, smaller right atrial volume and smaller tethering distance at baseline were independent predictors of TR reduction to ≤moderate at discharge (OR: 0.679; 95% CI: 0.537-0.858; P = 0.0012; OR: 0.722; 95% CI: 0.564-0.924; P = 0.0097). Fourteen subjects (2.5%) experienced a major adverse event at 30 days.Transcatheter tricuspid valve repair was found to be safe and effective in treating significant TR in a diverse, real-world population. (An Observational Real-World Study Evaluating Severe Tricuspid Regurgitation Patients Treated With the Abbott TriClip™ Device [bRIGHT]; NCT04483089).
Risk of recurrent stroke in Rotterdam between 1990 and 2020: a population-based cohort study
Authors: Bernhard P. Berghout, Daniel Bos, Peter J. Koudstaal, M. Arfan Ikram, M. Kamran Ikram
Journal: The Lancet Regional Health - Europe (2023)

After an initial stroke, current clinical practice is aimed at preventing recurrent stroke. Thus far, population-based estimates on the risk of recurrent stroke remain scarce. Here we describe the risk of recurrent stroke in a population-based cohort study.We included Rotterdam Study participants who developed a first-ever incident stroke during follow-up between 1990 until 2020. During further follow-up, these participants were monitored for the occurrence of a recurrent stroke. We determined stroke subtypes based on clinical and imaging information. We calculated ten-year overall and sex-specific cumulative incidences of first recurrent stroke. To reflect changing secondary preventive strategies employed in recent decades, we then calculated the risk of recurrent stroke within ten-year epochs based on first-ever stroke date (1990-2000, 2000-2010 and 2010-2020).In total, 1701 participants (mean age 80.3 years, 59.8% women) from 14,163 community-living individuals suffered a first stroke between 1990 and 2020. Of these strokes, 1111 (65.3%) were ischaemic, 141 (8.3%) haemorrhagic, and 449 (26.4%) unspecified. During 6585.3 person-years of follow-up, 331 (19.5%) suffered a recurrent stroke, of which 178 (53.8%) were ischaemic, 34 (10.3%) haemorrhagic and 119 (36.0%) unspecified. Median time between first and recurrent stroke was 1.8 (interquartile range 0.5-4.6) years. Overall ten-year recurrence risk following first-ever stroke was 18.0% (95% CI 16.2%-19.8%), 19.3% (16.3%-22.3%) in men and 17.1% (14.8%-19.4%) in women. Recurrent stroke risk declined over time, with a ten-year risk of 21.4% (17.9%-24.9%) between 1990 and 2000 and 11.0% (8.3%-13.8%) between 2010 and 2020.In this population-based study, almost one in five people with first-ever stroke suffered a recurrence within ten years of the initial stroke. Furthermore, recurrence risk declined between 2010 and 2020.Netherlands Organization for Health Research and Development, EU's Horizon 2020 research programme and the Erasmus Medical Centre MRACE grant.
The role of endosonography in cardiology: case series and literature review
Authors: Abdelrahman Elhakim, Kawther Karkour, Philip Sauter, Michael Rode, Mohamed Elhakim, Peter W Radke, Mohammed Saad
Journal:  (2023)

Abstract Aims Endosonography (EUS) is the diagnostic tool with the highest resolution for the local staging of gastrointestinal tumours and, due to the detailed visualization of the wall layers, is recommended in current guidelines for cancer management. In addition, an endoscope has an ultrasound tip design and balloon insufflation control design, and a 120° bending mechanism to deflect the endoscope tip. These advantages could be beneficial and valuable while investigating the cardiovascular structures during routine gastrointestinal procedures using this diagnostic tool. Methods and results We present six cases of incidentally diagnosed cardiac pathologies (pulmonary thromboembolism of the main pulmonary artery, patent foramen oval with right to left shunt under Valsalva, left atrial appendage thrombus, aortic dissection, moderate aortic valve stenosis, mitral and aortic valve endocarditis) during routine gastrointestinal endosonographic procedures. These diagnoses influenced changes in management strategies in four cases. Conclusion The introduction of EUS in cardiovascular medicine allows for a real-time high-resolution assessment of cardiovascular structures and allows early detection of silent cardiac pathologies during routine gastrointestinal procedures. It is the diagnostic tool with the highest resolution for accurate definition of variable gastrointestinal anatomy. Thus, help for accurate definitions of cardiovascular anatomy and pathology, which could influence optimal management strategies with improved safety, efficacy, and economic outcomes.
Targeting ACYP1-mediated glycolysis reverses lenvatinib resistance and restricts hepatocellular carcinoma progression
Authors: Shuai Wang, Lingyi Zhou, Ning Ji, Chengtao Sun, Linlin Sun, Jiao Sun, Yawei Du, Ningning Zhang, Yueguo Li, Weishuai Liu, Wei Lu
Journal: Drug Resistance Updates (2023)
Multi-omics blood atlas reveals unique features of immune and platelet responses to SARS-CoV-2 Omicron breakthrough infection
Authors: Hong Wang, Cuicui Liu, Xiaowei Xie, Mingming Niu, Yingrui Wang, Xuelian Cheng, Biao Zhang, Dong Zhang, Mengyao Liu, Rui Sun, Yezi Ma, Shihui Ma, Huijun Wang, Guoqing Zhu, Yang Lu, Baiming Huang, Pei Su, Xiaoyuan Chen, Jingjing Zhao, Hongtao Wang, Long Shen, Lixia Fu, Qianqian Huang, Yang Yang, He Wang, Chunlong Wu, Weigang Ge, Chen Chen, Qianyu Huo, Qingping Wang, Ying Wang, Li Geng, Yan Xie, Yi Xie, Lijun Liu, Jianwei Qi, Huaiyong Chen, Junping Wu, Erlie Jiang, Wentao Jiang, Ximo Wang, Zhongyang Shen, Tiannan Guo, Jiaxi Zhou, Ping Zhu, Tao Cheng
Journal: Immunity (2023)
Re: Judikael R. Saout, Gwendoline Lecuyer, Simon Léonard, et al. Single-cell Deconvolution of a Specific Malignant Cell Population as a Poor Prognostic Biomarker in Low-risk Clear Cell Renal Cell Carcinoma Patients. Eur Urol. 2023;83:441–51
Authors: Anna Reustle, Florian A. Büttner, Matthias Schwab, Elke Schaeffeler
Journal: European Urology (2023)
Summary Paper on the 2023 European Association of Urology Guidelines on the Management of Non-neurogenic Male Lower Urinary Tract Symptoms
Authors: Stavros Gravas, Mauro Gacci, Christian Gratzke, Thomas R.W. Herrmann, Markos Karavitakis, Iason Kyriazis, Sachin Malde, Charalampos Mamoulakis, Malte Rieken, Vasileios I. Sakalis, Natasha Schouten, Mark J. Speakman, Kari A.O. Tikkinen, Jean-Nicolas Cornu
Journal: European Urology (2023)
Re: Loren K. Mell, Stephanie L. Pugh, Christopher U. Jones, et al. Effects of Androgen Deprivation Therapy on Prostate Cancer Outcomes According to Competing Event Risk: Secondary Analysis of a Phase 3 Randomised Trial. Eur Urol. In press. https://doi.org/10.1016/j.eururo.2023.01.020
Authors: Jaehun Jung, Jae Heon Kim
Journal: European Urology (2023)